THROMBOPROPHYLAXIS

Thromboembolism Defined

In
deep vein thrombosis a blood clot forms in one of the
veins deep inside the leg. It can occur at any age but
is much more common in pregnant and older people. It can
be caused by a wide variety of factors other than air
travel. The clot may break away from its position and
travel through the heart to the lung - pulmonary
thrombosis, where it may cause severe symptoms which can
result in death.

Maternal Mortality Rates

Figure 1.
Pulmonary thromboembolism (PTE) is the most common
direct cause of maternal death in the UK.

(From Why Mothers Die 2000 - 2002: CEMACH)

Figure 2. Maternal Mortality from Pulmonary Embolism
occurred until 1980 but has remained static
subsequently.

(From Why Mothers Die
2000 - 2002: CEMACH)

Figure 3.
Pulmonary thromboembolism (PTE) - the incidence has been fairly constant
over recent years.

(From Why Mothers Die
2000 - 2002: CEMACH)

Pulmonary
thromboembolism (PTE) is the most common direct cause of maternal death in
the UK (Figure 1).
Successive reports on Confidential
Enquiries into Maternal Deaths have highlighted failures in recognising risk
factors for VTE and employing adequate prophylaxis. Although PTE remains the
leading cause of maternal death, in the latest Confidential Enquiry,
the proportion of postpartum
deaths following caesarean section had fallen, suggesting that adoption of
published recommendations1
may have had a beneficial effect.
However, no impact has been made over the last decade on reducing the four
to five deaths annually from antenatal PTE or the three deaths annually from
PTE following vaginal delivery (Figure 2).
In the most recent Confidential
Enquiries into Maternal Deaths, the majority of the women with fatal
antenatal PTE died in the first trimester and most postpartum deaths
followed vaginal delivery. Although
most VTE occurs antenatally, the risk per day is greatest in the weeks
immediately after delivery.9901

Risk Factors

Pregnancy is a risk factor for VTE
and is associated with a ten-fold increase compared with the risk for
nonpregnant women.SIGN
Some women are at even higher risk during pregnancy
because they have one or more additional risk factors:

Prevalence

In a study
of nearly 400,000 pregnancies0101

In a study of women in
Minnesota with deep venous thrombosis or pulmonary embolism first diagnosed
between 1966 and 1995,0501
including women with venous thromboembolism during pregnancy or the
postpartum period, the overall incidence of venous thromboembolism was 199.7
per 100,000 woman-years. The annual incidence was 5 times higher among
postpartum women than pregnant women and the incidence of deep venous
thrombosis was 3 times higher than that of pulmonary embolism . Pulmonary
embolism was relatively uncommon during pregnancy versus the postpartum
period (10.6 vs. 159.7 per 100,000). Over the 30-year study period, the
incidence of venous thromboembolism during pregnancy remained relatively
constant whereas the postpartum incidence of pulmonary embolism decreased
more than 2-fold.

Screening For Risk Factors

An
individual assessment of thrombotic risk should be undertaken, ideally
before pregnancy or in early pregnancy. This assessment should be repeated
if the woman is admitted to hospital or develops other intercurrent
problems.

Women at high risk of VTE, including
those with previous confirmed VTE, should be offered prepregnancy
counselling with a prospective management plan. Haematological screening for
congenital thrombophilia is not indicated.9701

Previous VTE - Investigation

Women with previous VTE have an increased risk of recurrence in
pregnancy.0502 The
probability of VTE during pregnancy without thrombosis prophylaxis was 6.2%.
There were no recurrences in the 44 women who had no evidence of
thrombophilia and who also had a previous episode of thrombosis that was
associated with a temporary risk factor. Among the 51 women with abnormal
laboratory results or a previous episode of idiopathic thrombosis, or both,
3 (5.9 percent) had an antepartum recurrence of venous thromboembolism (95
percent confidence interval, 1.2 to 16.2 percent).

Women with a previous VTE should have a careful
history documented and undergo screening for both inherited and acquired
thrombophilia, ideally before pregnancy. Women with previous VTE
should be screened for inherited and acquired thrombophilia ideally before
pregnancy.

Thromboprophylaxis during pregnancy and the puerperium

Expert haematological
advice or referral to a joint obstetric and haematology clinic should be
sought in cases when the antenatal team are uncertain about
thromboprophylaxis. Immobilisation of women during pregnancy, labour and the
puerperium should be minimised and dehydration should be avoided, regardless
of their risk of VTE.

Previous VTE and no
thrombophilia

Women with previous VTE and no thrombophilia should be
offered prophylaxis with low molecular weight heparin (LMWH) for six weeks
after delivery. There is some evidence that if the previous VTE was
associated with a temporary risk factor, such as trauma, antenatal
anticoagulation is not required.0001
In the study by
Brill-Edwards et al0001125
pregnant women with a single previous episode of venous thromboembolism were
prospectively studied. Antepartum heparin was withheld, but anticoagulant
therapy was given for four to six weeks post partum. There were no
recurrences in the 44 women who had no evidence of thrombophilia and who
also had a previous episode of thrombosis that was associated with a
temporary risk factor. Among the 51 women with abnormal laboratory results
or a previous episode of idiopathic thrombosis, or both, 3 had an antepartum
recurrence of venous thromboembolism. If the previous VTE was
oestrogen-related (pregnancy or the combined oral contraceptive pill) or if
there are additional risk factors such as obesity, thromboprophylaxis with
LMWH has been advocated. Women with previous VTE should be offered
postpartum thromboprophylaxis with LMWH. It may be reasonable not to use
antenatal thromboprophylaxis with heparin in women with a single previous
VTE associated with a temporary risk factor that has now resolved.
Women
who have had more than one previous episodes of VTE, who have had one
episode and in addition have a family history of VTE in a first degree
relative or whose episode of VTE was in an unusual site (such as the
axillary vein), all of which are markers for a thrombophilic state, should
be considered for antenatal thromboprophylaxis with LMWH.0401

Women with previous
recurrent VTE or a previous VTE and a family history of VTE in a
first-degree relative should be offered thromboprophylaxis with LMWH
antenatally and for at least six weeks postpartum.

Previous VTE and inherited
thrombophilia

Women with thrombophilias have an increased risk of
VTE in pregnancy0001,
0301
but this risk varies according to the specific
thrombophilia.0002

The risk also depends on
whether the woman or her close family have had a previous VTE.0003

Current evidence supports, and existing guidelines
recommend, that women with previous VTE and an identifiable thrombophilia
should receive antenatal thromboprophylaxis with LMWH; prophylaxis should
continue for six weeks postpartum.

Expert haematological
advice should be sought for women with symptomatic thrombophilia, as
specific thrombophilias, particularly AT deficiency, merit higher doses of
LMWH for thromboprophylaxis.

Prophylaxis

Enoxaprin

Normal
body weight (50-90 kg)

40 mg daily

Body weight < 50 kg

20 mg daily

Body weight > 90kg

40 mg 12 hourly

Higher prophylactic dose

40 mg 12
hourly

Therapeutic dose

1 mg/kg 12 hourly

Table 1. Antenatal prophylactic and therapeutic doses of
enoxaprin.

Inherited thrombophilia without
previous VTE

The risk of VTE associated with thrombophilia varies
considerably. Antithrombin deficiency is associated with a high risk (30%)
of VTE in pregnancy. Asymptomatic women with protein C or protein S
deficiencies have an eight-fold increased risk of VTE associated with
pregnancy but most events occur postpartum.9601

Data from retrospective family
studies confirm a high risk of VTE for women with homozygous factor V Leiden0102and combined defects of
factor V Leiden and prothrombin gene mutation.0103Women heterozygous for
the factor V Leiden mutation or the prothrombin gene variant are at
considerably lower risk.0002

Women should be treated
according to the level of risk associated with their thrombophilia. Since
the risk of VTE is lower in women with no history of VTE, antenatal
thromboprophylaxis is not always necessary, except in those with combined
defects, those homozygous for defects or those with antithrombin deficiency.9701,0002,
0102,
0103Women with
antithrombin deficiency should always receive thromboprophylaxis in
pregnancy and the puerperium.

Women with known inherited or acquired thrombophilia
may qualify for LMWH or warfarin for six weeks following delivery, even if
they were not receiving antenatal thromboprophylaxis if they have other risk
factors.

Women with asymptomatic inherited or acquired
thrombophilia may qualify for antenatal or postnatal thromboprophylaxis,
depending on the specific thrombophilia and the presence of other risk
factors.

Acquired thrombophilia (antiphospholipid syndrome)

Antiphospholipid syndrome (APS) is defined as the
presence of lupus anticoagulant or anticardiolipin antibodies of medium?high
titre on two occasions eight weeks apart, found in association with a
history of thrombosis (arterial or venous) or adverse pregnancy outcome
(three or more unexplained miscarriages before ten weeks of gestation, a
fetal death after ten weeks of gestation or a premature {less than 35 weeks}
birth due to severe pre-eclampsia or intrauterine growth restriction). The
risk of recurrent thromboses in women with APS is up to 70% and may be
even higher in pregnancy. Therefore, pregnant women with APS and previous
thromboses should receive antenatal and postnatal thromboprophylaxis with
LMWH.

The management of women with obstetric manifestations
of APS is controversial. Low-dose aspirin has been shown to improve
pregnancy outcome in APS and is recommended for all women with APS. However,
the presence of antiphospholipid antibodies with no previous ?APS
classifiable? pregnancy loss or thrombosis does not equate to APS and such
women do not require LMWH (or low-dose aspirin).9702,0004

Women with antiphospholipid syndrome identified
because of recurrent miscarriage may not require LMWH for six weeks
postpartum but should receive LMWH for at least three to five days,
especially if they have other risk factors.

No previous
VTE or thrombophilia

Data to support recommendations for many of the
individual risk factors listed in Table 1 is lacking.

Women should be reassessed before or during labour for
risk factors for VTE. Age over 35 years and BMI greater than 30/body weight
greater than 90 kg are important independent risk factors for postpartum VTE
even after vaginal delivery. The combination of either of these risk factors
with any other risk factor for VTE (such as pre-eclampsia or immobility) or
the presence of two other persisting risk factors should lead the clinician
to consider the use of LMWH for three to five days postpartum.

Clinical judgement is required with regard to the
weighting of the above risk factors. There are circumstances where one or
two risk factors alone may be sufficient to justify antenatal
thromboprophylaxis with LMWH, for example an extremely obese woman admitted
to the antenatal ward.

A woman with two current or persisting risk factors
should be considered for prophylactic LMWH for three to five days after
vaginal delivery.

In general, women with three or more current or
persisting risk factors (other than those with a previous VTE or a
thrombophilia should be considered for prophylactic LMWH antenatally and for
at least three to five days postpartum.

Timing and
duration of treatment

Pregnancy

As VTE during pregnancy has an equal distribution throughout
gestation,9901
if a decision is made to initiate
thromboprophylaxis antenatally, this should begin as early in pregnancy as
practical.SIGN
Once antenatal treatment is
initiated it should continue until delivery unless a specific risk factor is
removed or disappears.

Women with ovarian hyperstimulation syndrome (OHSS) require
thromboprophylaxis for at least the period of inpatient stay.

Women with multiple risk factors for VTE and at risk of OHSS
undergoing ovulation induction may also be considered for
thromboprophylaxis.

There is no direct evidence-based data to guide
thromboprophylactic advice for pregnant travellers. However, it seems
prudent that precautionary conservative measures advised for all travellers
should also be recommended in pregnancy. These include isometric calf
exercises (as increasingly advised on in-flight media by major airlines),
walking around the aircraft cabin when possible, avoiding dehydration by
drinking plenty of water/juices/soft drinks and by minimising alcohol and
caffeine intake. The case for aspirin would be empirical at this time.

Antenatal
thromboprophylaxis should begin as early in pregnancy as practical.

Puerperium

Postpartum thromboprophylaxis should be given as
soon as possible after delivery, provided that there is no postpartum
haemorrhage.

Those with postpartum haemorrhage should be fitted
with thromboembolic deterrent stockings.

If the woman has been given regional analgesia,
LMWH should be withheld until four hours after insertion or removal of
the epidural catheter (or six hours if either insertion or removal were
traumatic). The first postpartum dose can be given after insertion but
before removal of the epidural catheter.

Postpartum thromboprophylaxis is normally continued for six
weeks in high-risk women as the prothrombotic changes of pregnancy do not
revert completely to normal until several weeks after delivery.Women need to learn how to inject
themselves. However, for women at lower risk prophylaxis for three to five
days is usually recommended, despite the lack of evidence in this area. Low
risk includes those with two current or persisting risk factors as discussed
above (Table 1) and asymptomatic thrombophilias with low thrombotic risk
(heterozygous factor V Leiden and prothrombin gene variant). The risk of VTE
reduces when women are mobile postpartum but does not disappear. If the
woman is discharged home early, her thromboprophylaxis should be continued
at home, to complete the course of three to five days.

The combined oral contraceptive pill should not be
prescribed during the first three months postpartum for women with other
risk factors for VTE.

Risk factors may change. Therefore, puerperal women
undergoing surgery for any reason or those who develop severe infection or
who choose to travel long-haul are at increased risk of VTE even
though they may have been discharged from hospital following vaginal
delivery several weeks before.

Postpartum prophylaxis should begin as soon as
possible after delivery.

Agents for
Thromboprophylaxis

Low molecular weight heparin

Low molecular weight
heparins are the agents of choice for antenatal thromboprophylaxis. They are
as effective as and safer than unfractionated heparin in pregnancy.9201,
9703

Systematic reviews and
retrospective studies have concluded that LMWH is a safe alternative to
unfractionated heparin as an anticoagulant during pregnancy9902,0104 and
from a safety perspective LMWH is to be preferred.

The risk of
heparin-induced thrombocytopenia is reduced with LMWH.9503,
9703The
risk of heparin-induced thrombocytopenia is extremely low with LMWH
and has never been reported in
pregnancy, current guidelinessignstill recommend checking
the platelet count one week after starting LMWH.

Prolonged unfractionated heparin use during pregnancy may result in
osteoporosis and fractures9703
but this risk is low with LMWH.9902,
0005,
0104,0201

For postpartum
thromboprophylaxis, LMWH is probably the agent of choice for women who had
LMWH antenatally or for those requiring only three to five days of
postpartum treatment. Experience of enoxaparin in the puerperium reports no
adverse effects on the baby resulting from breastfeeding.9703

Low dose aspirin

Low-Low
dose aspirin is safe in pregnancy,9401 although its use for
thromboprophylaxis in this setting has never been assessed by a controlled
trial. One trial suggested that low-dose aspirin, compared with placebo,
reduces by 36% the risk of VTE after orthopaedic surgery, even in some women
taking concomitant heparin therapy.0006
Meta-analysis of trials in surgical and medical patients also shows a
significant reduction in deep vein thrombosis and pulmonary embolism with
antiplatelet prophylaxis.9402
The use of low-dose aspirin (75 mg daily) may, therefore, be appropriate in
situations where the risk of VTE is increased but is not deemed high enough
to warrant the use of antenatal LMWH; for example, in women with previous
provoked VTE without thrombophilia. Women should be advised of the lack of
evidence for benefit of aspirin use for thromboprophylaxis in pregnancy.

Warfarin

Warfarin
should be
Warfarin should be avoided if possible during pregnancy,SIGN
particularly between 6 and 12 weeks of gestation, because it is associated
with an up to 6.4% risk of teratogenesis and increases the risk of
miscarriage, fetal and maternal haemorrhage, neurological problems in the
baby and stillbirth.0007

Warfarin is safe after
delivery and for breastfeeding, although it requires close monitoring,
frequent visits to an anticoagulant clinic and carries an increased risk of
postpartum haemorrhage and perineal haematoma compared with LMWH. It is
inappropriate for women requiring only three to five days of postpartum
prophylaxis.

If the woman chooses to commence warfarin postpartum,
this can usually be initiated on the second or third postnatal day. LMWH
should be continued until the international normalised ratio is greater than
2.0.

Warfarin should usually
be avoided during pregnancy. It is safe after delivery and during
breastfeeding.

Dextran

Warfarin
should

Dextran should not be used primarily because of the
risk of anaphylaxis, which has killed fetuses by causing
massive histamine
release and uterine hypertonus.

Graduated elastic stockings

Graduated elastic
compression stockings may be used antenatally. There are no trials to
support such practice but the British Society for Haematology guidelines
give a grade C recommendation that all women with previous VTE or a
thrombophilia should be encouraged to wear class-II graduated elastic
compression below knee stockings throughout their pregnancy and for 6?12
weeks after delivery. Class-I thromboelastic stockings are appropriate for
hospital inpatients at increased risk of VTE and may be combined with LMWH.
Their use is also recommended for pregnant women travelling by air.

Labour and Delivery

Once the woman is in
labour or thinks she is in labour, she should be advised not to inject any
further heparin. She should be reassessed on admission to hospital and
further doses should be prescribed by medical staff.

The pregnancy-associated
prothrombotic changes in the coagulation system are maximal immediately
following delivery. It is, therefore, desirable to continue LMWH during
labour or delivery in women receiving antenatal thromboprophylaxis with
LMWH. For women receiving high prophylactic or therapeutic doses of LMWH,
the dose of heparin should be withheld if the woman goes into labour or
reduced to its thromboprophylactic dose on the day before induction of
labour or elective caesarean section and continued in this dose during
labour. If the woman is of normal weight, the dose for unfractionated
heparin should be 5000 units 12 hourly. For LMWH preparations, a once-daily
regimen should be adopted using the following doses: enoxaparin 40 mg,
dalteparin 5000 iu, tinzaparin 50 units/kg.

Epidural anaesthesia can
be sited only after discussion with a senior anaesthetist, in keeping with
local anaesthetic protocols. It is important to discuss the implication of
treatment with heparin or LMWH for epidural or spinal anaesthesia with the
woman before labour or caesarean section. To minimise the risk of epidural
haematoma, regional techniques should not be used until at least 12 hours
after the previous prophylactic dose of LMWH. When a woman presents while on
a therapeutic regimen of LMWH, regional techniques should not be employed
for at least 24 hours after the last dose of LMWH. LMWH should not be given
for at least four hours after the epidural catheter has been inserted or
removed and the cannula should not be removed within 10?12 hours of the most
recent injection.

The woman should receive a thromboprophylactic dose of
LMWH on the day before delivery by elective caesarean section,. On the day
of delivery, the morning dose should be omitted and the operation performed
that morning. The thromboprophylactic dose of LMWH should be given by three
hours postoperatively (or four hours after insertion or removal of the
epidural catheter, if appropriate). There is an increased risk of around 2%
of wound haematoma following caesarean section with both unfractionated
heparin and LMWH.

Women At Risk Of Haemorrhage

Women
Those at high
risk of haemorrhage with risk factors including major antepartum
haemorrhage, coagulopathy, progressive wound haematoma, suspected
intraabdominal bleeding and postpartum haemorrhage may be more conveniently
managed with unfractionated heparin. Unfractionated heparin has a shorter
half-life than LMWH and there is more experience in the use of protamine
sulphate to reverse its activity. If a woman develops a haemorrhagic
condition while taking LMWH, the treatment should be stopped and expert
haematological advice sought.
It should be remembered that excess blood loss and blood transfusion are
risk factors for VTE, so thromboprophylaxis should be commenced or
reinstituted as soon as the immediate risk of haemorrhage is reduced.

Thank you for choosing to visit us.

This is the personal website of David A Viniker MD FRCOG, retired Consultant Obstetrician and Gynaecologist - Specialist Interests - Reproductive Medicine including Infertility, PCOS, PMS, Menopause and HRT.I do hope that you find the answers to your women's health questions in the patient information and medical advice provided.

The aim of this web site is to provide a general
guide and it is not intended as a substitute for a consultation
with an appropriate specialist in respect of individual care and
treatment.

David Viniker retired from active clinical practice in 2012. In 1999, he setup this website - www.2womenshealth.com - to provide detailed
information many of his patients requested. The website attracts thousands of visitors every day from around the world.Website optimisation (SEO) has became more than an active hobby.
If you would like advice on your website, please visit his website Keyword SEO PRO or email him on david@page1-on-google.com.